Reference

Haematologica June 2019 104: 1176-1188; Doi:10.3324/haematol.2018.206375haematologica

Authors

Agraz-Doblas, Antonio and Bueno, Clara and Bashford-Rogers, Rachael and Roy, Anindita and Schneider, Pauline and Bardini, Michela and Ballerini, Paola and Cazzaniga, Gianni and Moreno, Thaidy and Revilla, Carlos and Gut, Marta and Valsecchi, Maria G. and Roberts, Irene and Pieters, Rob and De Lorenzo, Paola and Varela, Ignacio and Menendez, Pablo and Stam, Ronald W.

Abstract

B-cell acute lymphoblastic leukemia is the commonest childhood cancer. In infants, B-cell acute lymphoblastic leukemia remains fatal, especially in patients with t(4;11), present in ~80% of cases. The pathogenesis of t(4;11)/KMT2A-AFF1+ (MLL-AF4+) infant B-cell acute lymphoblastic leukemia remains difficult to model, and the pathogenic contribution in cancer of the reciprocal fusions resulting from derivative translocated-chromosomes remains obscure. Here, "multi-layered" genome-wide analyses and validation were performed on a total of 124 de novo cases of infant B-cell acute lymphoblastic leukemia uniformly diagnosed and treated according to the Interfant 99/06 protocol. These patients showed the most silent mutational landscape reported so far for any sequenced pediatric cancer. Recurrent mutations were exclusively found in K-RAS and N-RAS, were subclonal and were frequently lost at relapse, despite a larger number of non-recurrent/non-silent mutations. Unlike non-MLL-rearranged B-cell acute lymphoblastic leukemias, B-cell receptor repertoire analysis revealed minor, non-expanded B-cell clones in t(4;11)+ infant B-cell acute lymphoblastic leukemia, and RNA-sequencing showed transcriptomic similarities between t(4;11)+ infant B-cell acute lymphoblastic leukemias and the most immature human fetal liver hematopoietic stem and progenitor cells, confirming a "pre-VDJ" fetal cellular origin for both t(4;11) and RAS mut The reciprocal fusion AF4-MLL was expressed in only 45% (19/43) of the t(4;11)+ patients, and HOXA cluster genes are exclusively expressed in AF4-MLL-expressing patients. Importantly, AF4-MLL/HOXA-expressing patients had a significantly better 4-year event-free survival (62.4% vs 11.7%, P=0.001), and overall survival (73.7 vs 25.2%, P=0.016). AF4-MLL expression retained its prognostic significance when analyzed in a Cox model adjusting for risk stratification according to the Interfant-06 protocol based on age at diagnosis, white blood cell count and response to prednisone. This study has clinical implications for disease outcome and diagnostic risk-stratification of t(4;11)+ infant B-cell acute lymphoblastic leukemia

Description

En este artículo he liderado una investigación sobre la Leucemia Linfoblástica Aguda en pacientes menores de un año con translocación en los genes MLL y AF4. Para ello, hemos sido capaces de recopilar la mayor cohorte de pacientes de esta rara enfermedad, 124 pacientes de diferentes hospitales europeos: Hospital Erasmus MC-Sophia children (Rotterdam, Países bajos), Hospital Armand Trosseau (París, Francia) y el Hospital Pediátrico San Gerardo (Monza, Italia). En la actualidad, los pacientes con esta enfermedad tienen muy mal pronóstico, con una supervivencia libre de enfermedad menor al 10% en los 5 primeros años.
Este estudio ha permitido identificar: la frecuencia mutacional más baja reportada hasta la fecha en cualquier tumor humano, así como mutaciones frecuentes en los genes RAS y la presencia de inestabilidad genética en las muestras en el momento de la recaída. A pesar de la ausencia de alteraciones genéticas, las muestras de los pacientes con la reorganización MLL-AF4 muestran un perfil transcripcional único con múltiples rutas de señalización alteradas que ofrecen nueva información sobre los mecanismos moleculares implicados en el desarrollo de esta patología y que abren la puerta a nuevos estudios para el diseño de estrategias terapéuticas más útiles para el tratamiento de esta trágica enfermedad.
Además, el análisis combinado de los estudios genómicos y transcriptómicos, junto con la caracterización del repertorio de variantes del receptor de célula B expresado por las células linfoblásticas de los tumores nos han permitido determinar que la leucemia se origina en un precursor pro-B inmaduro que aporta el contexto epigenético necesario para que la translocación MLL-AF4 juegue su papel conductor de la leucemia.
Por último, hemos demostrado que la expresión del gen de fusión recíproco AF4-MLL regula la expresión de multitud de genes importantes para el desarrollo de la patología y se asocia a un mejor pronóstico en los pacientes con leucemia.

 

AntonioAgraz CV min

 

REFERENCIA DEL INVESTIGADOR

Antonio Agraz Doblas es graduado en Biotecnología con mención en Biomedicina por la Universitat Rovira i Virgili. Seguidamente, cursó el máster en análisis de datos ómicos en la Universitat de Vic. En 2018, se doctoró con sobresaliente Cum Laude en Biología Molecular y Biomedicina en la Universidad de Cantabria bajo la dirección de Ignacio Varela y Pablo Menéndez, donde su proyecto principal de tesis fue la caracterización genómica y transcriptómica de la Leucemia Linfoblástica Aguda pro-B en pacientes menores de un año con translocación en los genes MLL y AF4. Acabada su etapa formativa, ha trabajado como científico postdoctoral en el campo de la onco-hematología, contando con un total de nueve artículos científicos publicados en las más prestigiosas revistas internacionales, ha participado en congresos nacionales e internacionales y ha colaborado activamente en proyectos de divulgación científica. Recientemente, ha realizado un MBA en industria farmacéutica donde se está desarrollando en el departamento médico, consiguiendo una gran experiencia en comunicación médica y en gestión de proyectos.

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